Title:NF1, Neurofibromin and Gene Therapy: Prospects of Next-Generation Therapy
VOLUME: 20 ISSUE: 2
Author(s):Xi-Wei Cui, Jie-Yi Ren, Yi-Hui Gu, Qing-Feng Li* and Zhi-Chao Wang*
Affiliation:Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011
Keywords:Gene therapy, neurofibromatosis type 1, plexiform neurofibroma, malignant peripheral nerve sheath tumor, adeno
associated virus vector, neurofibromin.
Abstract:Neurofibromatosis type 1 [NF1] is an autosomal dominant genetic disorder affecting multiple
organs. NF1 is well known for its various clinical manifestations, including café-au-late macules,
Lisch nodules, bone deformity and neurofibromas. However, there is no effective therapy for NF1.
Current therapies are aimed at alleviating NF1 clinical symptoms but not curing the disease. By altering
pathogenic genes, gene therapy regulates cell activities at the nucleotide level. In this review, we
described the structure and functions of neurofibromin domains, including GAP-related domain
[GRD], cysteine-serine rich domain [CSRD], leucine-rich domain [LRD] and C-terminal domain
[CTD], which respectively alter downstream pathways. By transfecting isolated sequences of these
domains, researchers can partially restore normal cell functions in neurofibroma cell lines. Furthermore,
recombinant transgene sequences may be designed to encode truncated proteins, which is functional
and easy to be packaged into viral vectors. In addition, the treatment effect of gene therapy is
also determined by various factors such as the vectors selection, transgene packaging strategies and
drug administration. We summarized multiple NF1 gene therapy strategies and discussed their feasibility
from multiple angles. Different protein domains alter the function and downstream pathways of
neurofibromin.
